Diving Deeper into Cholesterol: Sterol Testing with Dr. Dayspring

One of the tests I came across to help figure out more of what’s going on with my cholesterol status was sterol testing. What this test does is measure particles in your blood that tell you whether the changes in your cholesterol are related to too much absorption or too much formation.

Unfortunately none of this was taught… or even available when I was in med school, so I didn’t know much about this. I haven’t seen much of any of this written in the paleo-sphere so I’m not sure how much awareness there is out there on this subject.

This lead me to watch hours of lectures put out by Dr. Dayspring on LecturePad.org, a free site anyone can join.

As I normally do, I took a series of notes that I’ll share with you. I plan on writing a post later synthesizing all of this a more digestible format, but until then, here are my raw notes.

Get ready to dive deeper into the cholesterol rabbit hole. Warning… it gets pretty dense.

According to the Framingham Offspring Study, people who are cholesterol hyperabsorbers are at increased risk of cardiovascular disease.

The markers of increased absorption are Campesterol, Sitosterol, and Cholestanol.

Apo E Genotype – People with E4s have hyperabsorption of cholesterol.

People with inactivating mutations of NPC1L1 are hypo-absorbers, and have a 13% reduction in total cholesterol and 12% reduction in LDL-C. They have a 53% relative risk of reduction of coronary heart disease.

Even with frequent metabolic syndrome and diabetes, a low cholesterol absorption was associated with fewer recurrent cardiovascular events, and especially with better survival in elderly cardiovascular patients.

Ezetimibe – Drug used to prevent absorption, significantly lowered plasma concentrations of both sitosterol and campesterol (markers of hyper-absorption) from baseline compared with placebo.

However with atorvastatin monotherapy, this actually caused an INCREASE in sitosterol and campesterol, meaning that while the statin DECREASED cholesterol synthesis, this lead to a compensatory INCREASE in absorption.

A combination of both Statin and Ezetimibe lead to a decrease in both sitosterol and campesterol markers.

Too much cholesterol build up in a cell can lead to problems because it forms crystals within the cell that can cause damage.

The storage form of cholesterol is a cholesteryl ester (CE). What this means is that a long chain fatty acid forms an ester bond at hydroxyl group of the free cholesterol. This makes the molecule non-polar.

Acyl CoA cholesterol acyl transferase (ACAT) is the enzyme that catalyzes this. This is present in all cells, but is mainly in the liver and intestinal.

This is the key step in the formation of chylomicrons by intestinal cells and VLDL particles by the liver.

Only free cholesterol can be absorbed by the liver from bile and by the intestine from the gut.

Cholesterol is a cycloalkane with a double bond at C5. If the double bond is removed (saturation), then it is called a stanol, or cholestanol. Stanols can be used as a functional food because these cannot be absorbed.

Sitostanol is a commercial product that people can buy to reduce cholesterol absorption.

In the whole animal, and presumably in humans, most cholesterol is synthesized and utilized in the extrahepatic organs.

Lathosterol and Desmosterol, markers of cholesterol hyper-synthesis, are typically found at a concentration of 1:1000 to cholesterol, but this is genetically dependent.

High cholesterol + high lathosterol and high desmosterol = cholesterol hyper-synthesis. Statins work remarkably well in this case.

High cholesterol + low lathosterol and low desmosterol = cholesterol hyper-absorber. You can also check the phytosterols directly to determine this.

The body desaturates cholesterol into a stanol when it doesn’t need it anymore. The liver converts cholesterol into cholestanol which then goes down into the bile acid pathway which is then excreted into the gut, so there are trivial amounts of cholestanol within the blood.

When cholesterol makes it to the gut via the biliary system, intestinal bacteria can convert it into cholestanol or coprostanol. Usually stanols are very poorly absorbed, so if you find cholestanol in the blood, then that tells you that the patient is a hyperabsorber.

Sterols and Cholesterol Homeostasis: Lecture 2

The intestine absorbs 55% of the cholesterol that is presented to it, but this can vary depending on genetics with a range of 29-81%. This has nothing to do with diet. Vegetarians have the same rate of absorption.

The average diet consists of 200-600 mg of cholesterol, and consumption has no substantial effect on coronary risk.

The majority of cholesterol (~85%) absorbed is endogenous biliary cholesterol, NOT ingested cholesterol.

Intestines convert absorbed cholesterol into chylomicrons and HDL to be brought to the liver.

At the enterocyte, the NPC1L1 absorbs cholesterol and phytosterols. Any unused cholesterol and phytosterol is excreted via ABCG5, and ABCG8.

Phytosterols are absorbed readily from the intestinal lumen, ARE NOT esterified (unless present in large numbers), and therefore ARE NOT internalized into HDL or chylomicrons, and so are excreted back into the intestinal lumen.

The easiest way for enterocytes to accumulate LARGE amounts of phytosterols is to have genetic variants of the ABCG5/G8 transporters that are not so effective at evicting the phytosterols, or even absence of the ABCG5/G8 transporters which will not allow eviction of phytosterols from the enterocytes.

If there are large enough amounts of phytosterols accumulated within the enterocyte, the phytosterols can be excreted into the serum on the surface of HDL particles.

One enough cholesterol is inside the cell, there is down-regulation of the NPC1L1 transporter, and less cholesterol is absorbed.

Sterols and Cholesterol Homeostasis: Lecture 3

The use of surrogate markers like xenosterols is qualitative in nature, however it is more affordable and convenient.

Cellular cholesterol precursors are also found in normal human plasma, at concentrations roughly 1:1000 of that of cholesterol.

Thus the plasma levels of lathosterol and desmosterol are commonly used as measures of the cholesterol biosynthetic activity of the individual.

Do not confuse entry of a sterol into the intestinal enterocyte with sterol absorption which refers to the incorporation of a sterol into a lipoprotein (initially a chylomicron and HDL) and entry into the systemic circulation

Only an unesterified sterol can enter an enterocyte via sterol influx transporters.

One internalized the sterol may or may not be esterified by ACAT

Unesterified sterols are usually exported back to the gut lumen by sterol efflux proteins. Some can attach to chylomicron or HDL surface layers

Esterified sterols (esters) enter the chylomicron core.

Cholestanol blood concentration is very well correlated with fractional cholesterol absorption measured by the fecal excretion of isotopic cholesterol and the isotopic nonabsorbed marker (silosterol). Cholestanol is produced by the body.

Since they cannot be synthesized by the human body and therefore result exclusively from absorption, phyosterols (silosterol and campesterol) are used as more reliable markers of cholesterol absorption.

Plasma levels of Sitosterol were raised little when intakes were increased greatly, and on fixed intakes they were constant from week to week.

On diets devoid of plant sterols, the plasma and feces rapidly became free of sitosterol.

Coprostanol is formed by the conversion of cholesterol to coprostanol in the gut by intestinal bacteria.

Phytosterols are trafficked within or on lipoproteins. They do not exist within the body as free molecules. Most often in HDL and LDL particles.

Because plasma phytosterols are carried in lipoproteins, it’s advocated that they are expressed as a ratio with total cholesterol to adjust for total cholesterol concentration.

On the other hand, using adjusted values is not correct in statin studies, as the decrease in total cholesterol can increase the phytosterol to cholesterol ratio even though there is no change in the phytosterol concentration.

The main disadvantage of using ratios is that they are difficult to interpret when used in correlation and regression models.

Plasma sterols being reported as absolute values vs as ratios with cholesterol

Since both cholesterol and plant sterols are carried by lipoproteins in the plasma, more lipoprotein particles are often present in the plasma of hypercholesterolemic subjects.

Therefore, it can be assumed that hypercholesterolemic subjects might have a higher absolute plasma concentration of plant sterols, even with the same dietary background or with a similar plant sterol absorption rate.

To improve the estimation of cholesterol or total sterol absorption, circulating plant sterol levels are often standardized by reporting the plant sterol to cholesterol ratio.

Dr. Dayspring sees trouble here, lipoprotein concentrations vary between individuals AND vary within the same individual.

In patients with familial hypercholesterolemia, not only are cholesterol concentrations significantly higher compared with normocholesterolemic controls, but those of the plant sterols/stanols and cholesterol precursors are also significantly higher.

However, after correction for serum concentrations of cholesterol, the ratios of plant sterols and cholesterol precursors no longer differ.

Some say it depends on the question being asked:

When investigating synthesis and absorption differences among two groups, one would like to be certain that these effects are independent of the cholesterol concentration and therefore values should be expressed relative to cholesterol (as a ratio).

However, investigating the relationship between absorption markers, synthesis markers, and cholesterol levels, the absolute sterol concentrations should be used due to the fact that normalizing or adjusting for total cholesterol would mean that you are masking the outcome variable you are interested in assessing.

Insulin resistant patients have higher levels of cholesterol synthesis markers (desmosterol and lathosterol) and lower levels of absorption markers (cholestanol and sitosterol). Will have better LDL-C response to statins.

Statin treatment may increase plant sterol concentrations in the plasma by increasing intestinal sterol absorption or by lowering the free cholesterol pool in the liver, which may result in decreased secretion of cholesterol and plant sterols into bile.

Ezetimibe Treatment

Significant correlations between the lathosterol:cholesterol ratio and cholesterol synthesis rates were observed

The pattern associated with the most CV risk is hyperabsorption with hyposynthesis of cholesterol.

When LDL-P (apoB) are elevated in the face of normal sterol values, there is a problem with overproduction (typically related to TG abnormalities) or a decreased clearance of ApoB particles (LDL receptor issues, defective apoB, PSCK9 gain of function)

After lifestyle modification, statins are always the first line LDL-P lowering therapy unless TG are > 500 mg/dL.

Statins

Had the most reduction in coronary events in cholesterol hypersynthesizers (4S study).

Almost no effect in coronary events in cholesterol hyperabsorbers.

The major effect of statins is to reduce cellular cholesterol synthesis, resulting in an up-regulation of LDL receptor activity, enhanced fractional clearance of LDL from plasma, and reduction in plasma LDL cholesterol levels.

These effects may be offset due to compensatory increase in absorption

Because ezetimibe significantly reduces intestinal cholesterol absorption, but increases synthesis, and because statins have the opposite effect, it would appear that combination therapy would be ideal.

Patients with high levels of cholesterol synthesis AND absorption displayed the most effective LDL-C lowering by statin monotherapy.

Patients with a low cholesterol synthesis AND a high level of absorption, or with a high level of synthesis AND a low level of absorption responded poorly to statin monotherapy.

Ezetemibe

Lipids in the gut lumen present to the microvilli as a biliary micelles

Ezetimibe inhibits the NPC1L1 transporter, preventing uptake of cholesterol from the gut lumen

Thus, the chylomicron the enterocyte excretes will be cholesterol depleted.

The chylomicron will go to the liver and will deliver it’s decreased amount of cholesterol.

Ezetemibe also blocks NPC1L1 activity at the hepatobiliary porter too, to decrease backward flux of cholesterol from the biliary system to the hepatocyte.

Because of the depleted cholesterol pool, this will cause upregulation of LDL Receptors, which will lower Apo B, LDL-C, Non HDL-C, and TG

There will also be reduced VLDL assembly and secretion in hepatocytes. Which will also reduce LDL-C, TG, ApoB, LDL-P, and Non HDL-C

Therapeutic doses of phyosterols and phytostanols displace cholesterol from the micellar nucleus, so less cholesterol is available in micelles for absorption

People who supplement with phytosterols expose their intestines to way more phytosterols than someone on a vegetarian diet

Apo E4 have higher incidence of cholesterol absorption.

Apo E3/E3 are considered normal

Regardless of genotype, administration of phytosterols there is significant reduction in total cholesterol and LDL cholesterol.

Higher plant STEROL intake in the form of supplements increases circulating levels of plant sterols, while plant STANOL supplementation decreases these levels.

The only phytostanol available is sitostanol, aka “Benecol”

If you’re not going to measure phytosterols in the blood, then you should recommend patients to take a stanol.

The observation that hyperabsorption of phytosterols can produce premature CAD and aortic stenosis in individuals with defects in ABCG5/8, raises the possibility that increased serum levels of phytosterols can contribute to CAD in the general population.

Results from the L. reuteri study suggest that deconjugation of intraluminal bile acids results in reduced absorption of non-cholesterol sterols and indicate that L. reuteri NCIMB 30242 capsules may be useful as an adjunctive therapy for treating hypercholesterolemia.

This is one of the main reasons I’ve incorporated VSL#3 into my regimen because each capsule contains 112.5 billion CFUs. Which comes close to the ELIXA numbers, considering you get 60 pills per bottle of VSL3.

I’m taking one capsule in the morning and one in the evening and plan to do this for at least 2 months. So I’m getting at least 225 billion CFU daily.

Looking through the ELIXA site, I can’t seem to find how many CFUs per daily dose they have. I see 500 billion for a 6 day course… and can’t figure out if that’s 500 billion total, or if that’s 500 billion per day.

Also.. their daily dose consists of 10 capsules. That seems like a lot of pills to take at once doesn’t it?

I watched all six videos. A lot of info, may need to watch them again. I did have these tests done in 2014 and according Boston Heart Diagnostics I was an over producer and an over absorber. Not in the fifth quadrant in either case, more like the low fourth quadrant.I don’t remember if they used absolute values or ratios in their analysis. If you look at the data in Dr. Daysprings graph these cases exist, kinda like the worst of both worlds. I am taking ezetimibe (Vitorin) twice a week. The only thing that has worked so far. Reducing saturated fat helped but not enough.

Amazing set of notes and understanding! There is very little information on the internet about how a body produces and absorbs cholesterol, probably due to the fact that it seems that only BostonHeart Diagnostics is one of the few diagnostics that monitors it.
I have a question…..on the outside, I am a fairly healthy 52 year old, father of 4,…who has over the last 9 years old has had a wife die in her sleep due to an aneurism caused by Coumadin, and then last year, lost my 16 year old daughter from Leukemia (diagnosed 4 years after her mom’s passing). During this time period, ultrasounds showed calcium deposits in the arteries and eyes, with blood numbers showing several values that were high, including LDL-C, Non-HDL-C and sdLDL-C.
After my daughter’s passing, I decided to focus on my own health to turn this hardening of my arteries, and started a following changed in nutritional regime:

The results after 6 months were very good and moved out of the danger. With the exception of the following
Product Marker Lathosterol went from 108 ==> 228 (above 160 dangerous)
Absorption Markers: Beta-Sitosterol 194 ==> 319 (above 180 danger), Campesterol 241 ==> 341 (above 160 danger)

My question (that my doctor could not answer), could the numbers for my absorption marker be due to the fact that in the last 6 months, I’ve added eating 2 avocados a day, 1 egg, teaspoon of brain octane? and should I be worried? and if yes, what should I do?

Firstly, condolences on the loss of your wife and daughter. Losing family members like that is absolutely terrible and my heart goes out to you.

Secondly, I have to admit that I’m not not well versed in how to interpret those numbers. It seems like you’ve wandered into similar territory as me where I found myself as both a hypersnyhesizer AND hyperabsorber.

Given your risk factors, and my lack of knowledge and expertise in this field, I really wouldn’t be able to comfortably offer you any advice. The best course of action would be to contact someone who actually knows what the heck they’re talking about like the lipidologist I saw, Dr. Dall.

Thank you.
If I learn something from BostonHeart or my doctor, I will keep you updated. I know I pushed a majority of my poker chips into the center with my new emphasis on the “good” fats, such as avocado, eggs, and coconut oil.
In good health, Eric

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